Adaptive designs in critical care trials: a simulation study.

BACKGROUND: Adaptive clinical trials are growing in popularity as they are more flexible, efficient and ethical than traditional fixed designs. However, notwithstanding their increased use in assessing treatments for COVID-19, their use in critical care trials remains limited. A better understanding of the relative benefits of various adaptive designs may increase their use and interpretation. METHODS: Using two large critical care trials (ADRENAL. CLINICALTRIALS: gov number, NCT01448109. Updated 12-12-2017; NICE-SUGAR. CLINICALTRIALS: gov number, NCT00220987. Updated 01-29-2009), we assessed the performance of three frequentist and two bayesian adaptive approaches. We retrospectively re-analysed the trials with one, two, four, and nine equally spaced interims. Using the original hypotheses, we conducted 10,000 simulations to derive error rates, probabilities of making an early correct and incorrect decision, expected sample size and treatment effect estimates under the null scenario (no treatment effect) and alternative scenario (a positive treatment effect). We used a logistic regression model with 90-day mortality as the outcome and the treatment arm as the covariate. The null hypothesis was tested using a two-sided significance level (α) at 0.05. RESULTS: Across all approaches, increasing the number of interims led to a decreased expected sample size. Under the null scenario, group sequential approaches provided good control of the type-I error rate; however, the type I error rate inflation was an issue for the Bayesian approaches. The Bayesian Predictive Probability and O'Brien-Fleming approaches showed the highest probability of correctly stopping the trials (around 95%). Under the alternative scenario, the Bayesian approaches showed the highest overall probability of correctly stopping the ADRENAL trial for efficacy (around 91%), whereas the Haybittle-Peto approach achieved the greatest power for the NICE-SUGAR trial. Treatment effect estimates became increasingly underestimated as the number of interims increased. CONCLUSIONS: This study confirms the right adaptive design can reach the same conclusion as a fixed design with a much-reduced sample size. The efficiency gain associated with an increased number of interims is highly relevant to late-phase critical care trials with large sample sizes and short follow-up times. Systematically exploring adaptive methods at the trial design stage will aid the choice of the most appropriate method.

Early Magnesium Treatment After Aneurysmal Subarachnoid Hemorrhage: Individual Patient Data Meta-Analysis.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Trials of magnesium treatment starting <4 days after symptom onset found no effect on poor outcome or DCI in SAH. Earlier installment of treatment might be more effective, but individual trials had not enough power for such a subanalysis. We performed an individual patient data meta-analysis to study whether magnesium is effective when given within different time frames within 24 hours after the SAH. METHODS: Patients were divided into categories according to the delay between symptom onset and start of the study medication: <6, 6 to 12, 12 to 24, and >24 hours. We calculated adjusted risk ratios with corresponding 95% confidence intervals for magnesium versus placebo treatment for poor outcome and DCI. RESULTS: We included 5 trials totaling 1981 patients; 83 patients started treatment<6 hours. For poor outcome, the adjusted risk ratios of magnesium treatment for start <6 hours were 1.44 (95% confidence interval, 0.83-2.51); for 6 to 12 hours 1.03 (0.65-1.63), for 12 to 24 hours 0.84 (0.65-1.09), and for >24 hours 1.06 (0.87-1.31), and for DCI, <6 hours 1.76 (0.68-4.58), for 6 to 12 hours 2.09 (0.99-4.39), for 12 to 24 hours 0.80 (0.56-1.16), and for >24 hours 1.08 (0.88-1.32). CONCLUSIONS: This meta-analysis suggests no beneficial effect of magnesium treatment on poor outcome or DCI when started early after SAH onset. Although the number of patients was small and a beneficial effect cannot be definitively excluded, we found no justification for a new trial with early magnesium treatment after SAH.

Improving patients' safety locally: changing clinician behaviour.

Safety initiatives in hospitals should focus on common health care interventions that when used appropriately can improve important health outcomes, and when used inappropriately or not at all, result in substantial harm. We suggest that errors of omission should be a safety priority. We focus on preventive health care interventions, and describe five steps that can improve patients' safety by changing clinician behaviour. The steps are to: do an environmental scan; understand current behaviour, target behaviour for change (why, what, when, where, and who); adopt effective strategies to change behaviour; and synergise.

Resuscitation fluid use in Australian and New Zealand Intensive Care Units between 2007 and 2013.

INTRODUCTION: Recent evidence indicates that the choice of intravenous fluids may affect outcomes in critically ill patients. METHODS: We recorded the administration of resuscitation fluids in patients admitted to Australian and New Zealand adult intensive care units (ICUs) for a 24-h period at 6 time points between 2007 and 2013. Changes in patterns of fluid use over this period were determined using regression analyses. RESULTS: Of the 2825 patients admitted to the 61 ICUs on the 6 study days, 754 (26.7%) patients received fluid resuscitation. Of those receiving fluid resuscitation, the proportion of patients receiving crystalloid significantly increased from 28.9% (41/142) in 2007 to 50.5% (48/95) in 2013 (adjusted odds ratio (OR) 2.93; 95% confidence intervals (CI) 1.35-6.33; p = 0.006); of these, the proportion of patients receiving buffered salt solutions significantly increased from 4.9% (7/142) in 2007 to 31.6% (30/95) in 2013 (OR 7.00; 95% CI 2.14-22.92; p = 0.001). The use of colloids significantly decreased from 59.9% (85/142) in 2007 to 42.1% (40/95) in 2013 (adjusted OR 0.34; 95% CI 0.16-0.74; p = 0.007) due to a significant decrease in the proportion of patients receiving gelatin; 28.9% (41/142) to 2.1% (2/95) (OR 0.10; 95% CI 0.03-0.29; p ≤ 0.001). CONCLUSION: Fluid resuscitation practice in Australia and New Zealand adult ICUs has changed over the 6-year study period. Crystalloid use increased primarily due to an increase in the use of buffered salt solutions while overall the use of colloid has decreased.

Barbiturate coma for severe, refractory vasospasm following subarachnoid haemorrhage.

OBJECTIVE: To document the outcome of patients treated with barbiturate coma for severe symptomatic angioplasty-resistant vasospasm. To compare mortality with that predicted by admission APACHE II score, and neurological outcome with that of historical controls treated with barbiturate coma for vasospasm, and with historical controls with delayed ischaemic deficits from vasospasm treated with nimodipine. DESIGN: Cohort study. SETTING: Neurosurgical Intensive Care Unit of tertiary referral university teaching hospital. PATIENTS: Eleven (6.7%) of 164 consecutive patients with aneurysmal SAH managed according to our protocol who were treated with thiopentone-induced burst suppression coma for severe symptomatic, angioplasty-resistant vasospasm. INTERVENTIONS: Chart, database and literature review. MEASUREMENTS AND RESULTS: All 11 patients survived to hospital discharge (mortality 0%) compared with first-day APACHE II predicted mortality of 30.6% (p=0.15). Outcome at 6 months was: good recovery 8/11 (72.7%), moderate disability 2/11 (18.2%), vegetative survival 1/11 (9.1%). Ten of 11 (90.9%) had a good neurological outcome compared with 50.6% of historical controls with delayed ischaemic deficit from vasospasm (odds ratio 9.78, 95% confidence interval 1.24-77.0, p=0.02), and 0% of previously reported patients treated with barbiturate coma for vasospasm (p < 0.01). CONCLUSION: Our results are better than previously published outcomes and suggest formal evaluation of barbiturate coma in the treatment of severe resistant symptomatic vasospasm following SAH is warranted.

Intensive care management of paediatric organ donors and its effect on post-transplant organ function.

OBJECTIVES: 1. To document the clinical course of paediatric beating heart organ donors. 2. To evaluate the effect of the ICU management of pediatric donors on the immediate function of transplanted organs. 3. To examine the validity of current donor selection criteria. DESIGN: Retrospective chart review and case series study. SETTING: Multidisciplinary ICU of tertiary referral paediatric hospital. PATIENTS: All patients who became solid organ donors between January 1980 and July 1990. OUTCOME MEASURES: 1. Incidence of major physiological abnormalities of the cardiovascular, pulmonary, renal and metabolic systems. 2. Number of organs retrieved and transplanted, reasons for non-transplantation of donated organs. 3. Immediate post-transplant function of transplanted organs. RESULTS: Seventy-seven organ donors were identified from whom 134 kidneys, 31 livers and 12 hearts were transplanted. Sixty (78%) patients developed diabetes insipidus. Sustained hypotension occurred in 41 (53.2%) and was commoner in patients treated with inotropic agents in the presence of a low central venous pressure and in patients with diabetes insipidus who did not receive anti-diuretic hormone replacement. Twenty-seven patients suffered at least one cardiac arrest. The data on post-transplant function were obtained for 129 kidneys (from 70 donors) 30 livers and 9 hearts. Fifty-two kidneys, 10 livers and 2 hearts were transplanted from donors who had suffered at least one cardiac arrest without apparent adverse effect on post-transplant organ function. Thirty-six kidneys from 31 donors suffered either acute tubular necrosis (ATN) or primary non-function. The donors of these organs spent longer in ICU (60.6 +/- 45.7 h versus 41.8 +/- 30.1 h p = 0.045) and had a higher mean maximum serum sodium concentration (163.4 +/- 10.9 versus 158.5 +/- 9.5 mmol/l p = 0.05) than those without these complications. The serum creatinine concentration and degree of inotropic support did not predict post-transplant function. Standard biochemical tests for hepatic function, the dose of inotropic agent received, time in ICU and incidence of hypotension did not predict post-transplant liver function. CONCLUSIONS: Aggressive fluid resuscitation and management of diabetes insipidus may promote stability in paediatric organ donors. Donor cardiac arrest does not alter the ICU course or compromise post-transplant organ function. The current criteria used for donor selection failed to predict post-transplant organ function and their use may increase organ wastage.

Delayed neurological deterioration following resection of arteriovenous malformations of the brain.

OBJECT: The aim of this study was to analyze delayed neurological deficits following surgical resection of arteriovenous malformations (AVMs). METHODS: The authors report on a consecutive series of 200 patients with angiographically proven AVMs of the brain that were surgically resected between January 1989 and June 1998. The 30-day mortality rate for patients in this series was 1%, with one death caused by AVM resection and one death attributed to basilar artery aneurysm repair following successful AVM resection. The Spetzler-Martin grading system correlated well with the difficulty of surgery. No permanent incidence of morbidity resulted from resection of Grade I or II AVMs; the percentage of patients with a significant neurological deficit due to resection was 7.8% for those with Grade III lesions and 33.3% for those with Grade IV or V AVMs. However, this grading system did not accurately predict the development of delayed neurological deficits. Ten patients (5%) developed delayed neurological deficits after recovering from anesthesia and surgery. The delayed deficit was due to hemorrhage in four of the 10 patients and all four had undergone resection of AVMs measuring at least 4 cm in diameter. An increase in blood pressure during the first 8 postoperative days precipitated hemorrhage in these patients. Edema arising as a consequence of propagated venous thrombosis (two patients) was associated with extensive venous drainage networks rather than large AVM niduses. Both hemorrhagic and edematous complications can be included under the umbrella term of "arterial-capillary-venous hypertensive syndrome" to describe the common underlying pathogenesis accurately. An additional four patients developed a delayed deficit as a result of vasospasm. Vasospasm occurred when resection had involved extensive dissection of proximal anterior and middle cerebral arteries; in such cases the incidence of vasospasm was 27%. CONCLUSIONS: On the basis of their analysis of these complications, the authors recommend strict blood pressure control for patients with lesions measuring 4 cm or more in diameter (particularly those with a deep arterial supply). Thromboprophylaxis with aspirin and heparin is prescribed for patients with extensive venous drainage networks, and prophylactic nimodipine therapy and angiographic surveillance for vasospasm are suggested for patients in whom extensive dissection of proximal anterior or middle cerebral arteries has been necessary.

Severe traumatic brain injury.

In western countries, injuries remain the leading cause of death in young adults (Jennett B. Epidemiology of head injury. J Neurol Neurosurg Psychiatry 1996; 60: 362-369). Worldwide, injuries are estimated to account for 15% of the burden of death and disability, and are projected to account for 20% in 2020 (Ad Hoc Committee on Health Research Relating to Future Intervention Options. Investing in Health Research and Development (Document TDR/Gen/96.1). Geneva: World Health Organisation, 1996). In developing countries road traffic injuries in particular are increasing in incidence and injuries are projected to be the third leading cause of death and disability worldwide by 2020 (Ad Hoc Committee on Health Research Relating to Future Intervention Options. Investing in Health Research and Development (Document TDR/Gen/96.1). Geneva: World Health Organisation, 1996). Head injury accounts for up to half of all deaths from trauma (Kraus J. Epidemiology of head injury. In: Cooper PR, Ed. Head Injury, 3rd ed. Baltimore, MD: William Wilkins, 1993), and in addition to causing death often causes severe and long-lasting functional impairment in survivors.

Aggressive management of aneurysmal subarachnoid haemorrhage based on a papaverine angioplasty protocol.

The aim of this study was to analyse the results of intensive therapy unit management of aneurysmal subarachnoid haemorrhage incorporating angioplasty in the protocol. Two hundred consecutive patients were treated using a detailed protocol that included nimodipine, early aneurysm repair, and surveillance angiography. Angiography was performed on days 5 to 7 (or when the clinical state suggested the presence of vasospasm). If angiographic vasospasm was identified, irrespective of whether clinical vasospasm was present or absent, papaverine was selectively administered. In patients with vasospasm blood pressure was elevated to 160-180 mmHg and selective papaverine administration was repeated daily until vasospasm resolved. In cases requiring more frequent administration of papaverine, or in whom papaverine failed to adequately reverse spasm, balloon angioplasty was considered and for clinically refractory cases barbiturate coma was introduced. 43% of patients underwent papaverine administration and of these the average number of separate papaverine procedures was four (maximum 23). 26% of patients developed neurological deficits though to be due to vasospasm whilst 17% underwent papaverine angioplasty without clinical signs of vasospasm. Twelve patients (6%) were entered into barbiturate coma. There was a 5.5% mortality and no difference in outcome between patients who developed angiographic vasospasm and those who did not. For those developing clinical vasospasm, 71% were independent and 10% were dead at follow up compared with 84% reaching independent grades and 4% dead in those not developing clinical vasospasm. These differences failed to reach a significant difference. The average Intensive Therapy Unit stay for aneurysmal subarachnoid haemorrhage patients was 13.1 days with a mean cost to the hospital of $AUD 24,379. This protocol appears to be both a clinically and cost effective method of managing aneurysmal subarachnoid haemorrhage.

International albumin use: 1995 to 2006.

Over the last ten years more reliable information regarding the risks and benefits of the use of albumin for fluid resuscitation has emerged. To determine what influence this has had on clinical practice, we sought to document albumin use (from mass of albumin supplied to hospitals) in 16 industrialised countries between 1995 and 2006. Data on national albumin and synthetic colloid use was sought from independent intensive care researchers and albumin issuers. The mass of albumin supplied per 10,000 persons on an annual basis by country and aggregated across the study countries was calculated. Volumes of synthetic colloid supplied per 10,000 persons were calculated. Data were obtained for 15 countries. Albumin use varied significantly between countries and throughout the observation period. Overall, aggregate albumin use decreased from a peak of 2.54 kg per 10,000 persons in 1995 to 1.40 kg per 10,000 persons in 1999; use has remained relatively constant since. Data on supply of synthetic colloids was available in only three countries and varied from 11.7 litres per 10,000 persons in Canada in 1995, to 231.8 litres per 10,000 persons in Denmark in 2004. Between 1995 and 1999 albumin use decreased and has been materially constant since; where data were available, use of synthetic colloids increased. Whether these practice changes have resulted in a net health gain or in harm requires further research.